In the United States, approximately 2.7 million people have chronic hepatitis C virus (HCV) infection, which is a significant clinical, social, and economic burden for the infected individual and for society as a whole. The outcome of a viral infection is determined by the interaction between the virus and the host immune response. Host genetic factors may also contribute to observed differences in disease prevalence, progression, and treatment response between the African American (AA) and non-Hispanic white (white) populations. Thus, we propose a comprehensive pharmacogenetic study to test the hypothesis that host genetic factors contribute to treatment response and disease progression of HCV infected individuals by examining a large number of immunological candidate genes. Specifically, we propose a two-stage design: initial testing with polymorphic markers spacing at 3-5kb for each of 15 candidate genes, followed by fine mapping of those genes selected based on statistical significance levels, number of significant markers, and results from a second sample. Three sets of samples will be used to evaluate response to therapy and/or disease progression: patients enrolled in the Virahep C trial (N=400), patients excluded from the trial but with disease progression information (N=400), and patients studied at NIDDK Liver Disease Section (N=400). The genetic association results from the latter sample will aid in decision making as to which genes to follow-up with fine mapping. We will also utilize multiple analytic approaches to evaluate associations between candidate genes and outcome variables: evaluating gene-gene interaction, and gene-viral/environmental factor interaction. In addition, we have built in strategies for controlling population stratification by genotyping additional population specific markers and evaluating population structure. By covering important candidate genes comprehensively, utilizing several samples, and explicitly testing possible confounding factors, this proposal maximizes the opportunity to identify the genes and their variants that contribute to the response to therapy and disease progression in HCV infection. As a result of identifying these host factors genetically and investigating their molecular interactions with HCV, we may gain additional insights into HCV pathogenesis and uncover new potential targets for vaccine development and therapy.